Emerging Therapies, Biologic Discoveries, and Improved QoL on Horizon for NETs

Diane Reidy Lagunes, MD

The treatment armamentarium of neuroendocrine tumors (NETs) is expanding to potentially include novel systemic therapies, a refined understanding of genetic changes in patients with pancreatic NETs, and improvements in surgical timing and quality of life (QoL), according to Diane Reidy Lagunes, MD.

For example, medical oncologists treating patients with NETs are more widely implementing patient-reported outcomes (PROs) to determine whether patients require symptom management or intervention with their treatment. Researchers are also studying whether all patients require surgical removal of their NET, even if they have slow-growing tumors.

Moreover, in early 2018, the field saw the FDA approval of Lutathera (lutetium [177Lu] oxodotreotide), a peptide receptor radionuclide therapy (PRRT) for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

“[The PRRT approval] will be the game changer for 2018 in terms of the clinical landscape. On the genetics or the biology side, though, there has been an explosion of technology, techniques and advancements that I am really excited about,” said Lagunes, who is associate deputy physician-in-chief of clinical operations and a medical oncologist at Memorial Sloan Kettering Cancer Center.

And, aside from these areas of promise, clinical trials are just beginning to evaluate possible activity with immunotherapy in patients with NETs, she added.

Reidy Lagunes shared insight on some of the emerging advancements in the NETs landscape in an interview withTargetedOncology^TMduring the 10th Annual NANETS Symposium. Additionally, she discussed what role, if any, exists for modern immunotherapies and chimeric antigen receptor (CAR) T-cell therapies in this landscape, and why somatostatin analogs (SSAs) continue to be a go-to choice to administer to patients.

Targeted Oncology^TM: What therapies do you see emerging in the field of NETs?Reidy Lagunes:We are really excited this year; NANETS has a record numbers of participants, which is a reflection of the recognition that this is a disease that we need our patients to be at the front and center [of]. I was honored to be part of the very first session, which was on emerging trends in NETs. There were 4 talks during my session.

The first one talked about patient-related outcomes, which is a super hot topic in the world of oncology and, essentially, it allows the patient to go online and tells us when they have symptoms. Then, as a result, we can intervene earlier and improve their QoL. From the beginning, PROs were going to be all about QoL. At the 2017 ASCO Annual Meeting, there was this really outstanding trial done by Dr Ethan Basch of UNC Lineberger Comprehensive Cancer Center, which showed that not only did early intervention in patients improve QoL, it actually improved survival.

By having an awareness of what patient symptoms may be earlier on, the hypothesis is that we can translate that into better outcomes—whether it’s because we're dose-reducing appropriately with chemotherapies they may be on, or we're getting on top of those symptoms. Bringing that into the NET arena and having those PROs will hopefully be a game changer. [This is] because many of our patients have a lot of symptoms, and if we can get on top of those symptoms earlier, we can hopefully improve quantity and quality.

The second talk was more on genetics—an interesting concept of pancreatic NETs—and how the cancer may change over time. [Researchers] essentially looked at pancreatic NETs and did some genetic sequencing of that, and they found that pancreatic NETs have certain chromosomal abnormalities that were much more profound than in any other solid tumor. We found the same in our study [we did on the topic], as well.

However, they took a step further and said, “When does this happen, and why? How does it potentially contribute to the evolution of the disease?” We know that if a patient is diagnosed with a cancer today, that cancer may look genetically very different 2 years from now. [The investigators] outlined very clearly what they think is happening in terms of when loss of heterozygosity potentially happens, and how that can interfere with the whole cell-cycle process—and thereby turn on the cancer to start to behave a little more aggressively. The hope and expectation is that we will be able to translate those findings into therapeutic outcomes to say, “OK, if we know the timing of when it happens, can we intervene earlier or later and change the outcomes of these patients?”

Dr Eric Nakakura of the University of California, San Francisco [led] our third presentation, and he focused on the surgical intervention of NETs with an emphasis of small bowel NETs. That is also, for the first time, a hot discussion. It used to be that people would say, “You can’t test surgery because patients just want to go to surgery.” In our disease, many clinicians may advocate for surgical debulking or removing some of the tumor, but not all of the tumor.

For some patients, that may be helpful. However, for some of them, if they are very slow-growing [tumors], they may not have ever needed it. [We could save] them an operation that has comorbidities with lots of adverse effects, potential risks, and long-term issues.

He talked about his surgical techniques, but there is a lot more discussion going on about [whether we] should do more trials to focus on the place for when surgery should come in—whether it’s sequencing. [This is] not necessarily “surgery or not,” because patients are so individualized, but maybe “when.” That is another hot area in NETs right now.

The last one, but not least, was on radio-labeled octreotide therapy and the Gallium-68 PET/CT DOTATATE scan and the role of nuclear medicine in treating and diagnosing our cancers. It is important to know that there is this new type of test. Having that does not improve our patients’ outcomes per se, and that is hard for patients because many of them think, "I have to get this Gallium scan.”

It is helpful for 2 reasons, but it doesn’t necessarily change their outcome. It is a fancier octreoscan and it’s a better scan. It uses less radiation and is less costly, but the Gallium-68 PET/CT DOTATATE scan is a very sensitive test that can pick up disease. It helps us detect where the cancers are located, and it helps us confirm if there is a certain receptor on the cancer. If that receptor is there when we inject the dye from the Gallium-68 PET/CT DOTATATE scan, it binds and then those tumors light up. The presence of those tumors lighting up—I tell my patients, “like a Christmas tree”—helps us better understand if the role of octreotide and potentially PRRT can be used for them. It is a helpful diagnostic test to see if a patient could potentially benefit from PRRT.

Dr Thomas Hope talked a bit about PRRT, which we hope is coming down the pipe. We should hear by early January 2018 from the FDA if it’s approved. The study was done only in small bowel NETs, but [Advanced Accelerator Applications, the manufacturer of Lutathera] is asking the FDA for approval for all NETs that are positive, and so we don’t know that the answer is going to be just in GEP-NETs. I don’t think there will be any more delays; it sounds like we are pretty much going to know by mid-January. It’s another opportunity for our patients, which is something that we are very much looking forward to.

We have seen the promise of PD-1/PD-L1 inhibitors across several malignancies. Is there any immunotherapy research being done in the NETs field?

The role of immunotherapy in NETs is still unclear. As you know, NETs are not all the same. Poorly differentiated neuroendocrine carcinomas [NECs] tend to be much more aggressive; they do respond to platinum-based therapy. However, generally, those tumors will become resistant quite quickly. For many years, we have sort of extrapolated from [cancer of the] small cell of the lung where there is a lot more patients. We would say anything that they do in small cell lung cancer [SCLC] we should do for our NECs.

Under the microscope, they look very similar; however, it turns out that, genetically, they are very different. Unfortunately, immunotherapies, for example, work very well in non—small cell lung cancers and some SCLCs, but we haven’t been able to prove that yet for this disease. We have trials that are ongoing that we're very excited about; I’m participating in a study with the University of California, San Francisco on that. There are other studies across the country that are looking at the extra pulmonary NECs. We're hoping that we may seem some signal, but we haven’t yet. Those studies are too early. There is promise there.

We also had another study with a PD-1 inhibitor that was across a couple institutions, and that was the PD-1 inhibitor for well-differentiated NETs. Those results are not yet available. The studies are ongoing, which are great. There are traditional genetic syndromes that are “home runs” for immunotherapies, such as Lynch syndrome or microsatellite-instability high—and we don’t usually have those types of inherited disorders in our patient population. However, there are other cancers that don’t have those and they’re responding, so we're still hopeful.

Does PD-L1 expression exist on NET cells?

Dr Matthew Kulke of Dana-Farber Cancer Institute did a study on that and did not find any PD-L1 expression or overexpression in these cancers. He did, interestingly, find PD-L2. There are no drugs right now that are targeting that, [and we don’t know] if that could potentially be a signal in that way, but it was interesting that there was that type of immunohistochemistry staining but not PD-L1.

Looking down the road, might there be interest in exploring CAR T-cell therapy?

Everyone, including our patients, are saying, “What about that?" It is pretty scary, but it is also very powerful. There are risks there, but it is truly miraculous what we're seeing in hematologic malignancies. Dr David C. Metz of the University of Pennsylvania [and colleagues] and been working [on this]. The challenge is what protein to try to use essentially to target the immune system to go on attack. That has been very laborsome, and there is still a lot of effort ongoing; we're not there yet.

There are many subtypes of NETs. Is there one in particular in which we may see have advancements over the next year?

With the approval of PRRT, that offers a huge opportunity for many of our patients who do well on octreotide (Somatostatin) or lanreotide (Somatuline Depot), but then the disease progresses. Then, we can often try everolimus (Afinitor) on some of those patients, but then we are stuck. We don’t have treatment options for them. That is going to give us something else in our armamentarium to help. The results were so striking and that is really exciting.

Our team recently submitted a paper that sort of characterizes how pancreatic NETs change over time—clinically and genetically—and more types of work like can help us better understand the different biology. We just can’t lump these NETs together. It is a disservice for everyone. With that in mind, as we focus the eye on the ball to this personalized approach, we are able to define them scientifically and biologically to then help give the treatment in a personalized way.

Will the role of SSAs change with the poised PRRT approval?

SSAs will always be what I tell my patients are “my first-string players.” They are, I believe, still the best drugs we have because they can control cancer with very minimal side effects. Everything that we do has to focus on the utility. Patients can live for so long, so when we need those drugs, we should use them. That is when the disease grows, or when the patients are symptomatic, or when we know they have a big burden of disease. To start with that drug—it [can be] a pain in the bottom once a month because that’s what it is—[it has] very little side effects to control a cancer for a long time.

Your question is a really good one in terms of, do we need to think about sequencing trials? How do we better understand how to give these drugs and when? It is such an important question, but it’s a hard one to answer. It kind of goes back to that personalized approach because patients are all so different that I don’t know if a randomized sequencing trial is going to give me the answer for the patient in front of me today because they are going to be different than the next person who comes along who may need another treatment.